1. Field of the Invention
This invention relates to nanoparticulate compositions comprising particles of an active agent and one or more cationic surface stabilizers adsorbed to the surface of the active agent. The nanoparticulate compositions have superior adhesion properties to biological surfaces, such as mucous, skin, hair, plant tissue, etc.
2. Description of the Related Art
Nanoparticulate compositions, which were first described in U.S. Pat. No. 5,145,684 (xe2x80x9cthe ""684 Patentxe2x80x9d), comprise a poorly soluble crystalline drug and a non-crosslinked surface stabilizer adsorbed to the surface of the drug. Nanoparticulate compositions are superior to macro-sized particulate drug formulations as nanoparticulate drug formulations can exhibit reduced toxicity and enhanced efficacy (U.S. Pat. No. 5,399,363), enhanced bioavailability (U.S. Pat. No. 5,662,883), and enhanced stability (U.S. Pat. No. 5,665,331). The ""684 patent teaches that ionic and non-ionic surface stabilizers are preferred for nanoparticulate compositions.
The ""684 patent describes a method of screening drugs to identify useful surface stabilizers that enable the production of a nanoparticulate composition. Not all surface stabilizers will function to produce a stable, non-agglomerated nanoparticulate composition for all drugs. Moreover, known surface stabilizers may be unable to produce a stable, non-agglomerated nanoparticulate composition for certain drugs. Thus, there is a need in the art to identify new surface stabilizers useful in making nanoparticulate compositions. Additionally, such new surface stabilizers may have superior properties over prior known surface stabilizers.
Exemplary known surface stabilizers useful in stabilizing and preventing the aggregation of nanoparticulate active agents are described in the ""684 patent. Known and particularly preferred surface stabilizers for nanoparticulate compositions include tyloxapol (U.S. Pat. No. 5,429,824), polyalkylene block copolymers (U.S. Pat. No. 5,565,188), sulfated non-ionic block copolymers (U.S. Pat. No. 5,569,448), high molecular weight, linear, poly(ethylene oxide) polymers (U.S. Pat. No. 5,580,579), butylene oxide-ethylene oxide block copolymers (U.S. Pat. No. 5,587,143), hydroxypropyl cellulose (U.S. Pat. No. 5,591,456), and sugar based surface stabilizers (U.S. Pat. No. 5,622,938).
Several prior art methods for minimizing nanoparticle aggregation following heat sterilization utilize non-ionic surface stabilizers and cloud point modifiers. Such methods include adding an anionic or cationic cloud point modifier to a nanoparticulate composition (U.S. Pat. No. 5,298,262); adding a non-ionic surface stabilizer and a non-ionic cloud point modifier to a nanoparticulate composition (U.S. Pat. No. 5,346,702); adding a non-ionic surface stabilizer and a charged phospholipid as a cloud point modifier to a nanoparticulate composition (U.S. Pat. No. 5,470,583); and adding a non-ionic surface modifier and a charged phospholipid to a nanoparticulate composition (U.S. Pat. Nos. 5,336,507 and 5,470,583).
Anionic and non-ionic surface stabilizers for nanoparticulate compositions have also been described. For example, U.S. Pat. No. 5,593,657 discloses nanoparticulate x-ray contrast compositions comprising anionic and non-ionic surface stabilizers. The nanoparticulate compositions adhere to the mucosal surface of the gastrointestinal tract (GIT), allowing for diagnostic examination of the GIT. U.S. Pat. No. 5,326,552 describes a nanoparticulate x-ray contrast composition having a high molecular weight non-ionic surface stabilizer and a cloud point modifier. In addition, U.S. Pat. No. 5,447,710 describes nanoparticulate x-ray contrast compositions having high molecular weight non-ionic surface stabilizers and a cloud point modifier.
Cationic surfactants are used in a wide variety of products and applications. For example, they are often used in cleaning, degreasing, and detergent compositions (U.S. Pat. Nos. 5,935,921, 5,935,272, and 5,912,219), liquid cleansers, bar soaps (U.S. Pat. No. 5,935,920), pesticides (U.S. Pat. No. 5,935,908), hair care products, such as shampoos and conditioners (U.S. Pat. Nos. 5,935,561, 5,932,535, and 5,932,202), laundry detergent (U.S. Pat. Nos. 5,935,271 and 5,929,024), photographic materials (U.S. Pat. No. 5,932,404), fabric softening compositions (U.S. Pat. No. 5,932,253), toothpaste compositions (U.S. Pat. No. 5,932,193), bleaching agents (U.S. Pat. No. 5,929,015), textile treatment compositions, automatic dishwashing detergent powders, cosmetics, environmental remediation (contaminated soil/groundwater remediation), enhanced oil recovery, and in medical applications, such as application to the lungs of premature infants.
There is a need in the art for effective, stable compositions having excellent adhesion properties to biological surfaces. The present invention satisfies these needs.
The present invention is directed to stable bioadhesive nanoparticulate compositions comprising an active agent and at least one cationic surface stabilizer. The active agent can be either crystalline, semi-crystalline, or amorphous, or liquid at or near room temperature. The active agent particles can be dissolved or dispersed in a liquid medium or used in dry form.
In one embodiment, described are stable bioadhesive nanoparticulate compositions comprising particles of a poorly water-soluble active agent and, adsorbed to the surface of the agent, at least one cationic surface stabilizer. The active agent can be either crystalline, semi-crystalline, or amorphous. The active agent particles of the nanoparticulate composition have an effective average particle size of less than about 4000 nm. The active agent particles can be dispersed in a liquid medium or used in dry form.
In yet another embodiment, described are stable bioadhesive nanoparticulate compositions comprising particles of a water-soluble active agent and, adsorbed to the surface of the agent, at least one cationic surface stabilizer. The active agent can be either crystalline, semi-crystalline, or amorphous. The active agent particles of the nanoparticulate composition have an effective average particle size of less than about 4000 nm. The active agent particles can be dispersed in a liquid medium or used in dry form.
In a further embodiment, described are stable bioadhesive nanoparticulate compositions comprising liquid particles of a poorly water-soluble active agent and, adsorbed to the surface of the liquid particles, at least one cationic surface stabilizer. The active agent is in a liquid state at or near room temperature. In this embodiment, the nanoparticulate composition is in the form of an emulsion. The active agent emulsion droplets of the nanoparticulate composition have an effective average particle size of less than about 4000 nm. The active agent emulsion droplets are dispersed in a liquid medium in which they are poorly soluble, such as water.
In a further embodiment, described are stable bioadhesive nanoparticulate compositions comprising liquid particles of a water-soluble active agent and, adsorbed to the surface of the liquid particles, at least one cationic surface stabilizer. The active agent is in a liquid state at or near room temperature. In this embodiment, the nanoparticulate composition is in the form of an emulsion. The active agent emulsion droplets of the nanoparticulate composition have an effective average particle size of less than about 4000 nm. The active agent emulsion droplets are dispersed in a liquid medium in which they are poorly soluble, such as mineral oil, vegetable oils (corn, safflower, olive, etc.), or a hydrocarbon.
Also described are stable bioadhesive nanoparticulate compositions comprising active agent particles dissolved or dispersed in liquid droplets of a poorly water-soluble liquid and, adsorbed to the surface of the liquid droplets, at least one cationic surface stabilizer. For this composition, the liquid droplets comprising active agent are dispersed in a liquid medium in which they are poorly soluble, such as water. In addition, the liquid droplets comprising active agent have an effective average particle size of less than about 4000 nm.
Yet another composition encompassed by the invention is a stable bioadhesive nanoparticulate composition comprising active agent particles dissolved or dispersed in liquid droplets of a water-soluble liquid and, adsorbed to the surface of the liquid droplets, at least one cationic surface stabilizer. For this composition, the liquid droplets comprising active agent are dispersed in a liquid medium in which they are poorly soluble, such as mineral oil, vegetable oils (corn, safflower, olive, etc.), or a hydrocarbon. In addition, the liquid droplets comprising active agent have an effective average particle size of less than about 4000 nm.
Another aspect of the invention is directed to pharmaceutical compositions comprising one or more nanoparticulate compositions of the invention. The pharmaceutical composition preferably comprises a nanoparticulate composition described above and a pharmaceutically acceptable carrier, as well as any desired excipients.
This invention further discloses methods of making nanoparticulate compositions according to the invention. A first method comprises contacting a nanoparticulate active agent with at least one cationic surface stabilizer for a time and under conditions sufficient to provide a stable nanoparticulate composition in which the cationic surface stabilizer is adsorbed to the surface of the active agent particles. The cationic surface stabilizer can be contacted with the active agent either before, during, or after size reduction of the active agent. The agent can be either crystalline, semi-crystalline, amorphous, or a mixture thereof. The active agent particles of the nanoparticulate composition have an effective average particle size of less than about 4000 nm. The effective average particle size can be achieved by wet milling techniques (such as described in the ""684 patent), by controlled precipitation methods, by homogenization, or by other suitable size reduction methods.
In cases where the active agent is in a liquid state at or near room temperature, the nanoparticulate composition is in the form of an emulsion. In such cases, a method of making the emulsion comprises combining the liquid active agent with an emulsifying agent and a liquid non-solvent and processing the resultant mixture with a homogenizer, high-shear mixer, rotor-stator type device, Microfluidizer(copyright), or other such equipment which is suitable for preparing emulsions and is well known to those skilled in the art. For this composition, the cationic surface stabilizer is adsorbed to the surface of the liquid active agent of the emulsion.
The invention also encompasses variations of this nanoparticulate emulsion formulation. For example, an active agent can be dissolved in a liquid droplet of an emulsion, or the active agent can be dispersed as a solid particle within a liquid droplet of an emulsion. In the first type of formulation, the liquid droplet in which the active agent is dissolved is dispersed within a liquid in which the liquid droplet is insoluble. In the second type of formulation, the active agent is dispersed within a liquid droplet of the emulsion; i.e., the active agent is insoluble in the liquid droplet of the emulsion. Moreover, the liquid droplets comprising the solid particles of the active agent are dispersed within a second liquid in which the liquid droplets are insoluble.
For these types of emulsion formulations, if the active agent nanoparticles are insoluble within the liquid droplets of the emulsion, then at least one cationic surface stabilizer is adsorbed to the surface of the active agent nanoparticles, the surface of the liquid emulsion droplets comprising the active agent particles, or a combination thereof. If, however, the active agent nanoparticles are soluble within the liquid droplets of the emulsion, then at least one cationic surface stabilizer is adsorbed to the surface of the liquid droplets comprising the active agent nanoparticles. The cationic surface stabilizers may be present during the emulsification process or may be added after the emulsion has been formed.
In a third method, aqueous nanoparticulate dispersions of water-soluble active agents may be prepared by encapsulating the active agent particles with a suitable coating and then dispersing them in water. The water-soluble nanoparticles may be prepared by wet milling in liquid nonsolvents, controlled precipitation, or other methods known to those in the art. After removal of the nonsolvents by evaporation, the nanoparticles may be treated with a protective coating, such as ethylcellulose, and subsequently dispersed in an aqueous vehicle. At least one cationic surface stabilizer is adsorbed to the encapsulated nanoparticles.
The present invention is further directed to methods of treatment comprising administering to an animal in need a therapeutically effective amount of a nanoparticulate therapeutic active agent/cationic surface stabilizer composition according to the invention. The active agent can be administered via any biological surface of the animal.
Yet another aspect of the invention is directed to the application of the described bioadhesive nanoparticulate compositions to any biological surface of an animal. Such application encompasses, for example, the application of nanoparticulate compositions useful as cosmetics, perfumes, shampoos, cleansers, moisturizers, deodorants, topical creams, ointments, nail polish, hair cosmetic compositions, etc.
The compositions of the invention can also be applied to plant tissue. Such methods include applying nanoparticulate compositions useful as fertilizers, pesticides, herbicides, etc. to a biological surface of a plant.
Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.